Journal
BLOOD
Volume 123, Issue 11, Pages 1720-1728Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-02-483495
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Funding
- Canadian Cancer Society (CCS)
- Human Frontiers Science Program Organization (HFSP)
- Genome-Quebec
- Fonds de Recherche du Quebec-Sante (FRQS) Cancer Research Network of the Leukemia Cell Bank of Quebec
- Canadian Center of Excellence in Commercialization and Research (CECR)
- Canada Foundation for Innovation (CFI)
- FRQS
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In mammals, combinatorial assembly of alternative families of subunits confers functional specificity to adenosine triphosphate (ATP)-dependent SWI/SNF-like Brg/Brm-associated factor (BAF) chromatin remodeling complexes by creating distinct polymorphic surfaces for interaction with regulatory elements and DNA-binding factors. Although redundant in terms of biochemical activity, the core ATPase subunits, BRG/SMARCA4 and BRM/SMARCA2, are functionally distinct and may contribute to complex specificity. Here we show using quantitative proteomics that BAF complexes expressed in leukemia are specifically assembled around the BRG ATPase. Moreover, using a mouse model of acute myeloid leukemia, we demonstrate that BRG is essential for leukemia maintenance, as leukemic cells lacking BRG rapidly undergo cell-cycle arrest and apoptosis. Most importantly, we show that BRG is dispensable for the maintenance of immunophenotypic long-term repopulating hematopoietic stem cells, suggesting that adroit targeting of BRG in leukemia may have potent and specific therapeutic effects.
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